Jakafi

"The U.S. Food and Drug Administration today expanded the approved use of Imbruvica (ibrutinib) to treat patients with chronic lymphocytic leukemia (CLL) who carry a deletion in chromosome 17 (17p deletion), which is associated with poor responses"...

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

Clinical Trials Experience In Myelofibrosis

The safety of Jakafi was assessed in 617 patients in six
clinical studies with a median duration of follow-up of 10.9 months, including
301 patients with myelofibrosis in two Phase 3 studies.

In these two Phase 3 studies, patients had a median
duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89%
of patients treated for more than 6 months and 25% treated for more than 12
months. One hundred and eleven (111) patients started treatment at 15 mg twice daily
and 190 patients started at 20 mg twice daily. In patients starting treatment
with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and
20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65%
and 25% of patients, respectively, required a dose reduction below the starting
dose within the first 8 weeks of therapy.

In a double-blind, randomized, placebo-controlled study
of Jakafi, among the 155 patients treated with Jakafi, the most frequent
adverse drug reactions were thrombocytopenia and anemia [see Table 11].
Thrombocytopenia, anemia and neutropenia are dose related effects. The three
most frequent non-hematologic adverse reactions were bruising, dizziness and
headache [see Table 10].

Discontinuation for adverse events, regardless of
causality, was observed in 11% of patients treated with Jakafi and 11% of
patients treated with placebo.

Table 10 presents the most common adverse reactions
occurring in patients who received Jakafi in the double-blind, placebo-controlled
study during randomized treatment.

Description of Selected Adverse Drug Reactions

Anemia

In the two Phase 3 clinical studies, median time to onset
of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient
( < 1%) discontinued treatment because of anemia. In patients receiving
Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to
2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually
recovered to reach a new steady state that was approximately 1.0 g/dL below
baseline. This pattern was observed in patients regardless of whether they had
received transfusions during therapy.

In the randomized, placebo-controlled study, 60% of
patients treated with Jakafi and 38% of patients receiving placebo received red
blood cell transfusions during randomized treatment. Among transfused patients,
the median number of units transfused per month was 1.2 in patients treated
with Jakafi and 1.7 in placebo treated patients.

Thrombocytopenia

In the two Phase 3 clinical studies, in patients who
developed Grade 3 or 4 thrombocytopenia, the median time to onset was
approximately 8 weeks. Thrombocytopenia was generally reversible with dose
reduction or dose interruption. The median time to recovery of platelet counts
above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of
patients receiving Jakafi and to 4% of patients receiving control regimens.
Discontinuation of treatment because of thrombocytopenia occurred in < 1% of
patients receiving Jakafi and < 1% of patients receiving control regimens.
Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting
Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to
patients with a platelet count greater than 200 X 109/L (17% versus 7%).

Neutropenia

In the two Phase 3 clinical studies, 1% of patients
reduced or stopped Jakafi because of neutropenia.

Table 11 provides the frequency and severity of clinical
hematology abnormalities reported for patients receiving treatment with Jakafi
or placebo in the placebo-controlled study.

a Presented values are worst Grade values
regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse
Events, version 3.0

Additional Data from the Placebo-controlled Study

25% of patients treated with Jakafi and 7% of patients
treated with placebo developed newly occurring or worsening Grade 1
abnormalities in alanine transaminase (ALT). The incidence of greater than or
equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4
ALT elevations.

17% of patients treated with Jakafi and 6% of patients
treated with placebo developed newly occurring or worsening Grade 1
abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST
elevations was < 1% for Jakafi with no Grade 3 or 4 AST elevations.

17% of patients treated with Jakafi and < 1% of
patients treated with placebo developed newly occurring or worsening Grade 1
elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was
< 1% for Jakafi with no Grade 3 or 4 cholesterol elevations.

Clinical Trial Experience In Polycythemia Vera

In a randomized, open-label, active-controlled study, 110
patients with polycythemia vera resistant to or intolerant of hydroxyurea
received Jakafi and 111 patients received best available therapy [see Clinical
Studies]. The most frequent adverse drug reaction was anemia. Table 12
presents the most frequent non-hematologic treatment emergent adverse events occurring
up to Week 32.

Discontinuation for adverse events, regardless of
causality, was observed in 4% of patients treated with Jakafi.

DRUG INTERACTIONS

Drugs That Inhibit Or Induce Cytochrome P450 Enzymes

Ruxolitinib is metabolized by CYP3A4 and to a lesser
extent by CYP2C9.

CYP3A4 inhibitors

The Cmax and AUC of ruxolitinib increased 33% and 91%,
respectively following concomitant administration with the strong CYP3A4
inhibitor ketoconazole in healthy subjects. Concomitant administration with
mild or moderate CYP3A4 inhibitors did not result in an exposure change
requiring intervention [see Pharmacokinetics].

Fluconazole

The AUC of ruxolitinib is predicted to increase by
approximately 100% to 300% following concomitant administration with the
combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg
once daily, respectively [see Pharmacokinetics].

CYP3A4 inducers

The Cmax and AUC of ruxolitinib decreased 32% and 61%,
respectively, following concomitant administration with the strong CYP3A4
inducer rifampin in healthy subjects. No dose adjustment is recommended;
however, monitor patients frequently and adjust the Jakafi dose based on safety
and efficacy [see Pharmacokinetics].